Bacterial meningitis

MANAGEMENT OF BACTERIAL MENINGITIS in children.

Dr. Arun K. M

JR IIIIMS.BHU

VARANASI

DEFINITIONS:• BACTERIAL MENINGITIS (BM): An acute purulent

infection of the cranial and spinal leptomeninges due to bacterial etiology.

• ENCEPHALITIS: Inflammation of the brain parenchyma.• MENINGOENCEPHALITIS: Inflammation of the

leptomeninges and the brain parenchyma. • ASEPTIC MENINGITIS: Refers to CSF findings consistent

with leptomeningeal inflammation but routine bacterial culture are negative.

INTRODUCTION:• Bacterial meningitis remains a major cause of mortality and neurological

sequelae worldwide. In India and other developing countries the mortality rate ranges from 16-32%.

• The community incidence of acute BM in India is not known. The exact etiological diagnosis is often not possible. There are limited studies from India regarding the etiology and epidemiological factors associated with BM.

• Delay in diagnosis and initiation of antimicrobial therapy can result in poor outcome. Since clinical signs of meningitis cannot always be relied upon, laboratory support is imperative to achieve an early diagnosis.

• Due to emergence of antimicrobial resistance recommendations for therapy are changing.

• Laboratory surveillance of isolates is crucial to identify for immunization, chart preventive strategies and to help formulate rational empirical treatment for potentially fatal BM.

ETIOLOGY: The etiology of BM is affected most by the age of the patient.

Neonate:Early-onset acquisition S. agalactiae, E.coli, K.pneumoniae, Enterococci,L. monocytogenes

Neonate:Late-onset infection S. aureus, Gram-negative enteric bacilli, P. aeruginosa

Age: 1–3 months Same as early-onset in neonate + S.pneumoniae, N. meningitidis, and H.influenzae type b.

Age: 3 months to 5 years S. pneumoniae, N. meningitidis and H. influenzae type b.

Age: >5 years children and adults S. pneumoniae and N. meningitidis.

RISK FACTORS:A major risk factor for BM is the lack of immunity to specific pathogens associated with young age.

PRECIPATING FACTORS ORGANISMS

Defects of complement system(C5-C8) and properdin system

Meningococcus

Splenic dysfunction or asplenia Pneumococcus, H.influenzae type b.

T-Lymphocyte defect(aids, cancer, chemotherapy and congenital)

Listeria monocytogenes

CSF leak and cochlear implants Pneumococcus

Lumbosacral dermal sinus and meningomyelocele

Staph. aureus, Gram negative entric bacilli e.g: E.coli, Klebsiella etc.

CSF shunts Coagulase negative Staphylococci, Staph. aureus.

PATHOGENISIS AND PATHOPHYSIOLOGY:• Bacteria reach the CNS either by hematogenous spread or by

direct extension from a contiguous site.• In neonates, pathogens are acquired from non- sterile

maternal genital and intestinal secretions.• Direct inoculation of bacteria into the CNS can result from

trauma, skull defects with CSF leaks, congenital dura defects such as a dermal sinuses or meningomyelocele, or extension from a suppurative parameningeal focus.

Bacteraemia Endothelial damage Bacteria in CSF

Permeability of blood-brain barrier

Leucocyte attraction and CSF entrance: meningeal inflammation

Cerebral vasculitis

Release of excitatory amino acidsaminoacids

Interstitial edema Cytotoxic edema

Intracranial pressure

Neuronal injury apoptosis

Vasogenic edema

Bloodstream volaemia

Global perfusion

Cerebral blood flow: Ischaemia

Pro-inflammatory cytokines

CLINICAL FEATURES:• Manifestations of BM depend on the age of the patient and

duration of disease.• In general, the younger the patient the more subtle and atypical

are the signs and symptoms.• Onset of acute BM has two forms :

i. The sudden onset rapidly progressive manifestation of shock, purpura, DIC, reduced level of consciousness leading to death in 24hrs.

ii. Common form with-

a. Non specific findings- fever(84%), headache(76%),vomiting(70%), anorexia(19%) , poor feeding, symptoms of URTI, myalgia, arthralgia, tachycardia, petechiae, rash etc.

b. Alteration in mental status like irritability, lethargy, stupor or coma(5%).

c. Seizure (20-30%): focal or generalised and as result of cerebritis,

infarction or electrolyte disturbance.

d. Signs of meningeal irritation(59%)- neck stiffness(65%), kernigs sign(27%) and brudzinski sign(51%).

e. Signs of increased ICT include headache, projectile vomiting, reduced (GCS≤8) or fluctuating level of conciousness, abducent nerve palsy, cushing’s reflex, un-equal dilated pupils, papilloedema, decorticate or decerebrate posturing, stupor, coma, signs of herniation.

g. Cranial neuropathy- Most common cranial nerves involved include 3rd, 6th, 7th and 8th.

h. Focal cerebral signs (20%) - due to cortical necrosis, occlusive vasculitis, cerebritis, abscess.

NEONATES

a) Neonates and infants have nonspecific signs like fever, hypothermia, irritability, lethargy and feeding difficulty.

b) Neurologic signs- Excited or depressed and bulging fontanel. Minor convulsions present as blinking eyes, fixed stare, facial twitching and sucking.

No clinical feature is diagnostic in isolation, and the most accurate combination of clinical features to rise or lower suspicion of meningitis is still unclear.

Pediatrics 2010; 126:952-960.

MANAGEMENT OF BACTERIAL MENINGITIS:Symptoms and signs of BM

Check airway, breathing &circulation; gain vascular access

Signs of shock and raised ICPManage accordingly

Perform diagnostic tests

Contraindication to LP Perform LP

YES

YES

NO

NO

YES

<3 months old ? CSF s/o meningitis

Empiric antibiotics for suspected meningitis:

i.v Cefotaxime + iv ampicillin

YES

YES NO

Do not delay antibiotic

Cont’d

Empiric antibiotic for suspected meningitis : i.v Cefetriaxone.

No role of steroids.

·Add vancomycin, if prolonged Or multiple antibiotic exposure within last 3 months

·If HSV meningoencephalitis in differential diagnosis give i.v acyclovir

Reduced or fluctuating conscious level or focal neurological signs

·Full volume maintenance fluid [Isotonic fluid-DNS or NS].

·Do not restrict fluid unless there is SIADH or raised ICT.

·Monitor fluid administration, urine output,electrolytes and blood glucose.

Antibiotics for confirmed meningitis.

·Close monitoring for signs of raised ICP ,shock and repeated review.

·If LP contra-indicated, perform delayed LP when no longer contra-indicated.

NO

NO YES

Perform CT scan

Specific pathogen identified

YES

Antibiotics for unconfirmed meningitis.

<3 months old?

Ceftriaxone ≥ 10 days

YES

i.v cefotaxime + ampicillin i.v for ≥14 days

NO

Initial management: • Check airway, breathing, circulation, disability (level of

consciousness) and environment (presence of rash, temperature control).

• Elective intubation and ventilation if necessary.• If signs of shock present manage accordingly with normal

saline boluses and vasopressor support.• Seizures managed with anticonvulsants like phenytoin and

midazolam.• After the patient has been stabilised further examination and

diagnostic tests performed.

Management of raised ICP. • Early intubation if; GCS <8, Evidence of herniation, Apnea,

Inability to maintain airway.• Mild head elevation of 15–30° (Ensure that the child is

euvolemic).• Hyperventilation: Target PaCO2: 30–35 mm Hg (suited for acute,

sharp increases in ICP or signs of impending herniation).• Mannitol: Initial bolus: 0.25–1 g/kg, then 0.25–0.5 g/kg, q 2–6 h

as per requirement, up to 48 hrs.• Hypertonic Saline: Preferable in presence of Hypotension,

Hypovolemia, Serum osmolality >320 mOsm/kg, Renal failure, Dose: 0.1–1 ml/kg/hr infusion, Target Na+−145–155 meq/L.

• Adequate sedation and analgesia.• Prevention and treatment of seizures: use Lorazepam or

midazolam followed by phenytoin as initial choice.• Avoid noxious stimuli: use lignocaine prior to ET suctioning

[nebulized (4% lidocaine mixed in 0.9% saline) or intravenous (1–2 mg/kg as 1% solution) given 90 sec prior to suctioning].

• Control fever: antipyretics, cooling measures.• Maintenance IV Fluids: Only isotonic or hypertonic fluids

(Ringer lactate, 0.9% Saline, 5% D in 0.9% NS), No Hypotonic fluids.

• Maintain blood sugar: 80–120 mg/dL.• Refractory raised ICP - Barbiturate coma, Hypothermia and

Decompressive craniectomy.

Routine investigations:• Complete blood count: Neutrophilia suggestive of bacterial

infection.• Serum glucose: Often low; allows interpretation of CSF glucose.• Electrolytes, urea, and creatinine :To assess for complications and

fluid management.• Coagulation studies: To assess for complications.• Blood cultures: Positive in 40–90% depending on the organism.• Inflammatory markers(CRP and procalcitonin): Elevation

suggestive of bacterial infection; procalcitonin(≥5ng/mL) of more value; neither can establish nor exclude diagnosis.

CEREBROSPINAL FLUID EXAMINATION.• CSF analysis and culture remains the definitive method for

diagnosis of BM.• Lumbar puncture (LP) should be performed when BM is

suspected. In neonates, meningitis accompanies sepsis in 20-25% of cases so procedure to be considered.

• If LP is delayed empirical antibiotic should be started within 1hr. • Contraindications to LP:

a. Absolute (lumbar puncture is not to be done)

i. Signs of raised intracranial pressure (papilloedema, decrebrate posturing)

ii. Local skin infection at the LP site.

iii. Evidence of obstructive hydrocephalus, cerebral oedema or herniation in CT (or MR) scan of brain

b. Relative (appropriate therapeutic measures and/or investigations are indicated before lumbar puncture)

i. Shock or hypotension ii. Coagulation disorder iii. Presence of focal neurological deficit, especially when

posterior fossa lesion is suspected. iv. Glasgow coma score of 8 or less. v. Continuing seizure activity.

NORMAL CSF VALUESNeonate Child

Total WBC (mm3) ≤20 <5

DLC-NEUTROPHILS Up to 5% none

Protein (mg/dL) <100 10-40

Glucose (mmol/L) ≥2.1 ≥2.5

CSF/serum glucose ≥0.6 ≥0.6

Typical CSF Parameters in Patients with Meningitis

Pathogen White blood cells per μL

Percentage of neutrophils

Glucose level

Protein level in mg per dL

Positive CSF stain

Pyogenic > 500 > 85-90 Low > 100-200 ~70 percent

L. monocytogenes > 100 >50 Normal > 50 ~30 percent

Partially treated pyogenic

> 100 >80 Normal > 70 ~60 percent

Aseptic, often viral

10 to 1,000 Early: > 50Late: < 20

Normal Normal or < 100

Not applicable

Tubercular 50 to 500 < 30 Low > 100 Rare

Fungal 50 to 500 < 30 Low Varies High in cryptococcus

CSF = cerebrospinal fluid.

• Early in illness, CSF cell count can be normal despite a positive CSF culture.

• Glucose concentration usually is decreased with a CSF to serum glucose ratio of 0.6 or less in neonates and 0.4 or less in children older than 2 months of age.

• Gram stain is positive in 80-90% of untreated cases with lower limit of detection of about 105 CFU/mL.

• CSF culture not routinely recommended because the yield decreases (80 to <50%) soon after antibiotic therapy (except gram negative Enteric bacilli) and isolates recovered are frequently contaminants.

• CSF cell count and glucose and protein concentrations generally remain abnormal for several days even after initiating appropriate antibiotic therapy.

• Latex agglutination tests and PCR to detect bacterial capsular antigens is useful in some patients with prior antibiotic therapy.

• Traumatic LP makes interpretation difficult. Leukocytes and protein are affected; gram stain, culture and glucose are not affected. A more accurate method is to calculate the predicted CSF WBC count by this formula.

Peripheral WBC/RBC count× CSF RBC count = CSF WBC count

Other tests on CSF: • Latex agglutination : Rapid; not 100% specific or diagnostic.

Latex agglutination depends on laboratory availability; including N. meningitidis, S. pneumoniae, H. influenzae type b, Escherichia coli and group B streptococci.

• PCR: Rapid; good sensitivity, techniques improving. PCR depends on laboratory availability; including N. meningitidis, S. pneumoniae, H. influenzae type b, L. monocytogenes, HSV, CMV, Enterovirus and Mycobacterium tuberculosis.

• Lactate : Routine use not currently recommended

INDICATION FOR REPEAT LP:• Lack of clinical improvement in 48-72 hrs.• Meningitis caused by resistant S. pneumonia strains or by

gram negative enteric bacilli.• In neonate with gram negative bacillary meningitis,

examination of CSF during treatment after 48-72 hrs of initiation of treatment is necessary to verify that culture are sterile.

DO NOT PERFORM REPEAT LP IF: Who are receiving appropriate antibiotics and making good

clinical recovery. Before stopping antibiotic therapy if patient is clinically well.

RADIALOGICAL DIAGNOSIS:• Cranial computed tomography (CT) is of limited use in acute

BM. CT in cerebral oedema may show slit-like lateral ventricle and areas of low attenuation.

• Diffuse meningial enhancement may be seen.• The main indications for a CT scan in meningitis when it is

preferred as a first line investigation prior to LP are:

a. Signs of ↑ICT (e.g. papilloedema)

b. Suspecting malignancy( focal neurological deficits).

c. Deteriorating neurological status.

d. Previous neurosurgical procedure or trauma.

e. Immunocompromised.• Normal CT scan does not exclude the risk of raised ICT.

DIFFERENTIAL DIAGNOSIS OF ACUTE BACTERIAL MENINGITIS:

• Other infective meningitis or meningoencephalitis (viral, tuberculous, fungal and parasitic).

• Focal infection (Brain abscess, subdural emphysema, cranial and spinal epidural abscess).

• Non infective illness ( malignancy, collagen vascular syndrome and exposure to toxins).

Clinical Decision Rules to Distinguish Bacterial from Aseptic Meningitis in Children with CSF Pleocytosis*

Rule Bacterial Meningitis Score Meningitest

Exclusion criteria 1. Neurosurgical history

2. Immunosuppression

3. CSF red blood cell count ≥ 0.01 × 106

per μL

4. Antibiotic use in the previous 48 hours

5. Purpura

1. Neurosurgical history

2. Immunosuppression

3. CSF red blood cell count ≥ 0.01 × 106 per μL

4. Antibiotic use in the previous 48 hours

Criteria (further evaluation, including lumbar puncture, is needed in patients with one or more findings)

1. Positive CSF Gram stain

2. Seizure

3. Blood neutrophil count ≥ 10,000 per μL

4. CSF neutrophil count ≥ 1,000 per μL

5. CSF protein level ≥ 80 mg per dL

1. Positive CSF Gram stain

2. Seizure

3. Purpura

4. Toxic appearance (irritability, lethargy, or low capillary refill)

5. CSF protein level ≥ 50 mg per dL

6. Serum procalcitonin level ≥ 0.5 ng per mL

Sensitivity (95% confidence interval)

99 percent (99 to 100) 100 percent (96 to 100)

CSF = cerebrospinal fluid. Curr Opin Neurol. 2009;22(3):292

*—White blood cell count ≥ 10 per μL

Antibiotic management:

i. Key is to start promptly.

ii. Antibiotic choice is based on

-Ability of CSF penetration and its concentration.

-Bactericidal property.

Penetration and estimated bactericidal power of antibiotics used for treatment of bacterial meningitis:

Antibiotic CSF penetration Bactericidal power* against

β- lactam susceptible pathogens

β- lactam resistant pathogens

Penicillin/ampicillin 5–15% 1–10 <1

Chloramphenicol >20% >10 NA

Cefotaxime/ceftriaxone 5–15% >10 1–10

Cefepime/meropenem 5–15% >10 1–10

Vancomycin <5% 1–10 1–10

Fluoroquinolones >20% >10 >10

Rifampicin >20%*concentration in CSF over the minimal bactericidal concentration against the isolated pathogen.

Recommended initial empiric selection of antibiotics for previously healthy children with suspected bacterial meningitis, by age and epidemiological situation

Patients Likely pathogens AntibioticNeonate-Early-onset acquisition

S agalactiae, E. coli,K pneumoniae, enterococci,L monocytogenes

Ampicillin+cefotaxime/amikacin

Neonate-Late-onset infection

S aureus, gram-negativeenteric bacilli, P aeruginosa

Nafcillin (flucloxacillin) orVancomycin+ceftazidime ± amikacin

Age: 1–3 months Same as early-onset in neonate+ S pneumoniae, N meningitidis,and H influenza

Ampicillin+cefotaxime or ceftriaxone

Age: 3 months to 5 years

S pneumoniae, N meningitidis,and H influenzae

Cefotaxime or ceftriaxone

Age: >5 years children and adults

S pneumoniae and N meningitidis.


In areas with moderate or greater prevalence of resistant S pneumonia

Multi-resistant pneumococci Cefotaxime or ceftriaxone + vancomycin(consideraddition of rifampicin)

Suggested pathogen-specific antimicrobial therapy for children with bacterial meningitis

Bacteria Antibiotic of choice Other useful antibiotics

N. meningitidis Penicillin G or ampicillin Cefotaxime or ceftriaxone

H. Influenzae type b Cefotaxime or ceftriaxone Ampicillin, chloramphenicol

S. pneumoniae:Penicillin-susceptible (MIC<0·1 mcg/mL)Penicillin-intermediate(MIC=0·1–1·0 mcg/mL)

Penicillin-resistant(MIC>1·0 mcg/mL)

Cephalosporin-resistant(MIC>0·5 mcg/mL)

Penicillin G, ampicillin Cefotaxime or ceftriaxoneplus vancomycin whenMIC >0·5 mcg/mLCefotaxime or ceftriaxoneplus vancomycin

Cefotaxime or ceftriaxoneplus vancomycin


Cefepime or meropenem

Cefepime or meropenemplus vancomycin

Adding rifampicinNew fluoroquinolones?

L. monocytogenes Ampicillin+gentamicin Trimethoprim-sulfamethoxazole

S. agalactiae Penicillin G+gentamicin Ampicillin+gentamicin

Enterococcus species Ampicillin+aminoglycoside Vancomycin+aminoglycoside

Enterobacteriaceae Cefotaxime or ceftriaxone Cefepime or meropenem

P. aeruginosa Ceftazidime+aminoglycoside Cefepime or meropenem

MIC=minimum inhibiting concentration.

Guidelines for the duration of antibiotic therapy.

Pathogen Suggested durationOf therapy(days)

H. influenza 5-7

N. meningitides 7-10

S. pneumonia 10-14

L. monocytogenes ≥21

Group B streptococci 14-21

Gram-negative bacilli (other than H. influenzae)

21or 2 wks beyond 1st sterile culture (whichever is longer)

Adjunctive and supportive treatment:1. Fluid management: {NICE clinical guidelines 2012 and Starship children’s health clinical

guidelines 2009}i. Resuscitation with normal saline bolus if required.ii. Fluid therapy should focus on avoiding hypovolemia and hypo-

osmolality.iii. Fluid type should be 0.9% NaCl with 5% dextrose (10% may require in

infants).iv. Give full volume maintenance fluids with appropriate adjustment for

ongoing losses unless there is SIADH or raised ICT.v. Hyponatremia at presentation can usually be assumed to be dilutional ,

on the basis of elevated level of ADH. Increased ADH is due to• Appropriate secretion to compensate for hypovolemia or to

maintain cerebral perfusion in the presence of cerebral edema → Full volume maintenance fluid.

• Inappropriate secretion due to brain damage and which might contribute to further brain damage → Restriction of fluid may be needed.

vi. Ongoing management • Frequent clinical review, including a careful assessment of

volume status.• Check serum sodium 6-12hrly depending on the initial sodium

level, ongoing fluid losses, clinical status and whether there is fluid restriction in place.

• In hyponatremia child on fluid restriction, fluid can be increased slowly as condition improves and serum sodium normalises.

There is evidence to support not restricting fluid for children in

developing countries where death rate are high and disease is

often advanced at presentation.

{The Cochrane Library 2011, issue 2}

2. Role of steroids and glycerol:

1. Corticosteroids significantly reduced hearing loss and neurological sequelae, but did not reduce overall mortality. Data support the use of corticosteroids in patients with bacterial meningitis in high-income countries, but no beneficial effect in low-income countries. {Cochrane database sys rev. 2010 sep;8(9).

2. Adjunctive dexamethasone in the treatment of acute bacterial meningitis does not seem to significantly reduce death or neurological disability. The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven. {Lancet Neurol. 2010 Mar;9(3)}

3. No significant difference was seen in neurological or hearing outcome with use of either glycerol or dexamethasone in children with acute bacterial meningitis.

{Indian Pediatr. 2007 Sep;44(9) }

4. With bacterial meningitis, the child's presenting status and young age are the most important predictors of hearing impairment. Little relief is obtained from current adjuvant medications like dexamethasone and glycerol.

{Pediatrics. 2010 Jan;125(1)}

COMPLICATIONS:

1.Early complications:• Ventriculitis.• Fluid and electrolyte disturbance.• SIADH.• Seizures.• Increased ICP.• Cranial nerve palsies.• Stroke.• Cerebral or cerebellar herniation.• Thrombosis of the dural venous sinuses.• Sub-dural effusion and empyema.• Prolonged fever or secondary fever.

2. Late complications:• Hearing loss.• Mental retardation.• Recurrent seizures.• Delaying accusation of language.• Visual impairment.• Behavioural problems.• Hydrocephalous.

PROGNOSIS:

Factors affecting the outcome

1) Age.

2) Etiology.

3) CSF findings at the time of diagnosis- concentration of bacteria or its products, WBC count and glucose concentration (<20mg/dL).

4) Time to sterilization of CSF after start of therapy.

5) Decreased level of consciousness.

6) Seizures occurring during hospitalization.

7) Presence of comorbid conditions

PREVENTION: 1.VACCINATION- • Immunisation is the most effective means of prevention BM in

children.• IAP recommends routine use of Hib vaccine in children with

efficacy rate against invasive infection ranges from 70-100%.• IAP recommends pnemococcal and meningococcal vaccination

for high risk children as vaccines under special circumstances.• Only meningococcal polysaccharide (MPSV) is avalaible.

Minimal age- 2 yrs. Revaccination only once after 3yrs in those at continued high risk.

• Minimum age for administration- 6wks for pnemococcal conjugate vaccine(PCV) and 2yrs for polysaccharide vaccine(PPSV). Administer 1 dose of PCV to all children aged 24 through 59mts who are not immunised for age. PPSV revaccination only once after 35yrs only in certain high risk patients.

• PCV must be offered to premature and low birth weight infants.• S.agalactiae vaccinaton for pregnant women in future.

Chemoprophylaxis for Bacterial MeningitisPathogen Indication Antimicrobial agent Dosage Comments

Neisseria meningitidis (postexposure prophylaxis)

Close contact (for more than eight hours) with someone with N. meningitidis infection Contact with oral secretions of someone with N. meningitidis infection

Rifampin Or

Adults: 600 mg every 12 hours for two daysChildren one month or older: 10 mg per kg every 12 hours for two daysChildren younger than one month: 5 mg per kg every 12 hours for two days

Not fully effective and rare resistant isolates

Ciprofloxacin (Cipro) Or

Adults: single dose of 500 mg Rare resistant isolates

Ceftriaxone (Rocephin) Single intramuscular dose of 250 mg (125 mg if younger than 15 years)

__

Haemophilus influenzae (postexposure prophylaxis)

Living in a household with one or more unvaccinated or incompletely vaccinated children younger than 48 months

Rifampin 20 mg per kg per day, up to 600 mg per day, for four days

___

Streptococcus agalactiae (group B streptococcus; women in the intrapartum period)

Previous birth to an infant with invasive S. agalactiae infectionColonization at 35 to 37 weeks’ gestationBacteriuria during pregnancyHigh risk because of fever, amniotic fluid rupture for more than 18 hours, or delivery before 37 weeks’ gestation

Penicillin G Or

Initial dose of 5 million units intravenously, then 2.5 to 3 million units every four hours during the intrapartum period

Clindamycin susceptibility must be confirmed by antimicrobial susceptibility test

If allergic to penicillin: Cefazolinor

2 g followed by 1 g every eight hours

Clindamycin (Cleocin)or

900 mg every eight hours

Vancomycin 15 to 20 mg per kg every 12 hours

Am Fam Physician. 2010;82(12):1491-1498.

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